Poxviruses are the largest known animal viruses. They are DNA viruses that replicate entirely in the cytoplasm. The 191-kbp genome is a double-stranded DNA molecule whose ends are covalently connected by single-stranded hairpin loops of 101 nucleotides. The sequences that form the hairpins are AT-rich and lie at the ends of 12-kbp inverted terminal repetition elements that contain short direct repeats and several open reading frames.
Poxviruses infect most vertebrates and invertebrates, causing a variety of diseases of veterinary and medical importance. The one large family (Poxyiridae) has two main subfamilies, the chordopoxyirinae, which infect vertebrates, and the entomopoxyirinae, which infect insects. Humans are the sole hosts of two poxviruses, variola virus (smallpox virus) and molluscum contagiosum virus, although many members of Orthopoxvirus, Parapoxvirus, and Yatapoxvirus can infect both animals and humans. Vaccinia virus is the virus used in the variola virus vaccine, and it is widely used as a model poxvirus.
At least two variants of variola virus are known, and they cause two forms of smallpox: variola major, with a case fatality rate of 30-40%, and variola minor, with a much reduced fatality rate of about 1%. At the genome level, the two variants are very similar. Thus, essentially all of the encoded proteins are nearly identical.
Essential viral enzymes have frequently proven to be good targets for antiviral drugs (for example, HIV reverse transcriptase and protease).
The E9 DNA polymerase, required for DNA replication, acts in concert with accessory proteins to attain efficient processive synthesis. Accessory proteins include the A20 protein, D4R, and others. The viral DNA polymerase is an established drug target, as exemplified by azidothymidine (AZT), which inhibits the HIV reverse transcriptase, and acyclovir, which is efficiently phosphorylated by the herpes simplex virus viral thymidine kinase, resulting in a triphosphate that preferentially inhibits viral DNA polymerase.
Naturally occurring variola virus has been eradicated from the planet. Given the virulence of this virus and its ability to spread in a population, the consequences of an intentional release of variola virus could be devastating. Official stocks of the virus are closely held, but it is not known whether undeclared stocks exist, so it is difficult to assess the current degree of risk. Safer vaccines and therapeutics that can mitigate the consequences of infection would together provide a strong deterrent to any intentional release.